Pharmaceutical composition including pimobendan

ABSTRACT

A solid formulation includes pimobendan or a pharmaceutically acceptable salt thereof, which is homogenously dispersed with a polyvalent acid and a flavor suitable to animals.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Nonprovisionalapplication Ser. No. 13/802,989, filed 14 Mar. 2013 and entitled“Packaging Assembly for Pharmaceutical Composition IncludingPimobendan,” which claims priority to U.S. Nonprovisional applicationSer. No. 13/402,292, filed 22 Feb. 2012 and entitled “PharmaceuticalComposition Comprising Pimobendan,” which claims priority to U.S.Nonprovisional application Ser. No. 11/072,207, filed 4 Mar. 2005 andentitled “Pharmaceutical Composition Comprising Pimobendan,” whichclaims priority to German Patent Application No. 102004011512, filed on8 Mar. 2004. The disclosure of each aforementioned application isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to the field of animal health. In particular, theinvention relates to novel oral pharmaceutical compositions comprising,as part of the pharmaceutically active compounds, pimobendan.

BACKGROUND OF THE INVENTION

Pimobendan,(4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazone)is disclosed in U.S. Pat. No. 4,361,563, herein incorporated byreference in its entirety. Pimobendan is a cardiotonic, hypotensive andanti-thrombotic. Said substance is useful in the treatment of congestiveheart failure.

Pimobendan hardly dissolves in water. The resorption of pimobendan whenadministered orally is prone to considerable inter- and intra-individualfluctuations if the active substance is incorporated in known orconventional pharmaceutical forms for oral administration. The reasonfor this is that pimobendan is characterized by a low solubility inaqueous media and a very highly pH-dependent solubility. To overcomethis, hard gelatine capsules were used containing pimobendan formulatedwith citric acid, in particular at a weight ratio of pimobendan tocitric acid of between 1:10 and 1:20 (U.S. Pat. No. 5,364,646, hereinincorporated by reference in its entirety). However, the high quantityof citric acid and the acidic taste of citric acid is not readilyaccepted by most animals—thus, such capsules have to be force-fed to theanimals or mixed with food prior to application.

The problem underlying the present invention was to provide a pimobendansolid formulation readily acceptable by mammalian subjects, especiallysmall animals.

SUMMARY OF THE INVENTION

The invention relates to novel solid formulations comprising as apharmaceutically active compound pimobendan or a pharmaceuticallyacceptable salt thereof which is homogenously dispersed in a polyvalentacid and a flavor acceptable to small animals. Preferably, such solidformulations are granules or tablets. Most preferred is a tabletcharacterized in that the tablet comprises, 1.25 mg, 2.5 mg, 5 mg or 10mg pimobendan, and further comprises lactose, corn starch,croscarmellose-sodium, citric acid, preferably at an amount of 50 mg/gof the solid formulation, artificial beef flavor, polyvidone, colloidalanhydrous silica and magnesium stearate.

The invention further relates to fluid-bed granulation processes forproduction of the solid formulations comprising the following steps:

-   -   a) an aqueous solution of pimobendan and a binder as defined        above is sprayed onto a solid carrier bed comprising one or more        carriers and/or excipients, flavor and citric acid anhydride and    -   b) the resulting mixture is dried and    -   c) the dried mixture is sieved and de-agglomerated and    -   d) a flow regulator is added to the sieved and de-agglomerated        mixture and    -   e) a lubricant is added to the resulting mixture and    -   f) the resulting mixture with lubricant is blended for        uniformity of granules to obtain final granules and/or    -   g) the final granules are compressed to solid formulations.

Step g) is omitted if the solid formulation is a granule. If the solidformulation is a tablet, step g) is carried out.

Furthermore, the invention relates to a method of prevention and/ortreatment of diseases wherein cardiotonic, hypotensive andanti-thrombotic substances have a therapeutic benefit, comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a solid formulation prepared as described above.

Preferred is a method of prevention and/or treatment of congestive heartfailure, comprising administering to a mammal in need of such treatmenta therapeutically effective amount of a solid formulation according tothe invention as disclosed above. Most preferably, the method comprisesadministering a tablet according to the invention, as defined above.

Furthermore, the invention relates to a method for manufacturing amedicament for the prevention and/or treatment of congestive heartfailure, Additionally, the invention relates to a method formanufacturing a medicament for the prevention and/or treatment ofcongestive heart failure, characterized in that a tablet comprising 1.25mg, 2.5 mg, 5 mg or 10 mg pimobendan and further comprising lactose,corn starch, croscarmellose-sodium, 50 mg/g citric acid, artificial beefflavor, polyvidone, colloidal anhydrous silica and magnesium stearate ismade.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Illustration of the basic top spray fluid bed process. Referencesigns: 1 Exhaust air ventilator; 2 Filter; 3 Pump; 4 Stirrer; 5 AqueousSuspension of micronized pimobendan and binder solution (PVP, HPMC,starch, gelatin); 6 Heating device for inlet air; 7 Sieve; 8 Nozzle,aqueous suspension is sprayed onto powder bed (citric acid, lactose,starch, flavor); 9 Powder bed.

FIG. 2: Flow Chart of Manufacturing Process.

FIG. 3: Dissolution Profiles, Pimobendan 1.25 mg tablets, showing 95%confidence intervals of the mean; USP apparatus 2 (Paddle), RotationSpeed 75 rpm, Buffer pH 4.0. Comparison of dissolution profiles oftablets which were stored 1 and 6 months at 40° C./75% in HDPE bottles;batch no. PB020049.

FIG. 4: Dissolution Profiles, Pimobendan 1.25 mg tablets, showing 95%confidence intervals of the mean; USP apparatus 2 (Paddle), RotationSpeed 75 rpm, Buffer pH 4.0. Comparison of dissolution profiles oftablets which were stored 12 days at 25° C./60% in open glass bottles;batch no. PB010080.

FIG. 5: Dissolution Profiles, Pimobendan 2.5 mg tablets, showing 95%confidence intervals of the mean; USP apparatus 2 (Paddle), RotationSpeed 75 rpm, Buffer pH 4.0. Comparison of dissolution profiles oftablets which were stored 3 and 6 months at 40.degree. C./75% in Alu-AluBlister; batch no. PB010076

FIG. 6: Dissolution Profiles, Pimobendan 5.0 mg tablets, showing 95%confidence intervals of the mean; USP apparatus 2 (Paddle), RotationSpeed 75 rpm, Buffer pH 4.0. Comparison of dissolution profiles oftablets which were stored 6 months at 40° C./75% in HDPE bottles; batchno. PB020059.

FIG. 7: Dissolution Profiles, Pimobendan 5.0 mg tablets, showing 95%confidence intervals of the mean; USP apparatus 2 (Paddle), RotationSpeed 75 rpm, Buffer pH 4.0. Manufacturing variable: Differentcompression forces; batch no. PB020205.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention it must be noted that asused herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “a tablet” includes aplurality of such tablets, reference to the “carrier” is a reference toone or more carriers and equivalents thereof known to those skilled inthe art, and so forth. Unless defined otherwise, all technical andscientific terms used herein have the same meanings as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. All given ranges and values may vary by 1 to 5% unlessindicated otherwise or known otherwise by the person skilled in the art.Accordingly, the term “about” is not used in the description.

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, the preferred methods, devices, and materials are described.All publications mentioned herein are incorporated herein by referencefor the purpose of describing and disclosing the substances, excipients,carriers, and methodologies as reported in the publications which mightbe used in connection with the invention. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

The solution to the above technical problem is achieved by thedescription and the embodiments characterized in the claims.

To overcome the difficulties in the art, a process was invented. Onlythe invention of this novel, fluid-bed granulation process allowed theformulation of solid formulations according to the invention. With theprocess according to the invention, it was possible to formulate along-term stable, capable of being produced on a large scale,homogenously dispersed, fast-releasing solid formulation. Despite thelarge size, pimobendan was homogenously dispersed. Such solidformulations comprise a flavor suitable for small animals, whichsurprisingly still allows a formulation having a polyvalent acid and yethave a palatibility rate of more than 70%—in many cases more than 90%.Thus, the solid formulations according to the invention are a major stepforward in therapeutic application as they do not have to be force-fedto the animal.

In a first important embodiment, the invention relates to a solidformulation, comprising pimobendan or a pharmaceutically acceptable saltthereof, see e.g. U.S. Pat. No. 4,361,563 or U.S. Pat. No. 5,364,646(both herein incorporated by reference in its entirety), which ishomogenously dispersed in a polyvalent acid selected from the groupconsisting of citric acid, acetic acid, maleic acid, tartaric acid andthe anhydride of any of said polyvalent acids and mixtures thereof, anda flavor acceptable to small animals. Such flavors according to theinvention preferably are selected from artificial beef flavors,artificial chicken flavors, pork liver extract, artificial meat flavor,honey flavor and the like. Said flavors not only disguise the taste ofthe polyvalent acid, but also the taste of pimobendan.

Preferably, the solid formulation according to the invention is a tabletor granule formulation. The granule formulation according to theinvention is explained in more detail below. More preferably, the solidformulation is chewable.

The invention preferably also relates to a solid formulation accordingto the invention, further comprising one or several pharmaceuticallyacceptable excipients. Excipients according to the invention arepreferably selected from the group consisting of diluents,disintegrants, carriers, binders, flow regulators, lubricants andsolvents. Any other excipients known to the skilled person and foundsuitable for the solid formulation according to the invention may alsobe comprised in the solid formulation according to the invention. Seealso Remington, J. P. The science and Practice of Pharmacy (2000). 20thed. Lippincott Williams & Wilkins Publishers, Philadelphia, US. Morepreferably, said excipients are carriers/disintegrants selected from thegroup lactose, starch, cellulose, microcrystalline cellulose andcellulose derivatives, e.g. methylcellulose, and the like. Any othercarrier known to the skilled person and found suitable for the solidformulation according to the invention may also form part of the solidformulation according to the invention. See also Remington, J. P. Thescience and Practice of Pharmacy (2000). 20th ed. Lippincott Williams &Wilkins Publishers, Philadelphia, US.

One or several binders according to the invention are preferablyselected from the group consisting of polyvidone (used synonymously forpovidone), methylcellulose, hydroxypropylmethylcellulose (HPMC),hydroxymethylcellulose, starch, gelatin, and the like. Any other binderknown to the skilled person and found suitable for the solid formulationaccording to the invention may also be comprised in the solidformulation according to the invention. See also Remington, J. P. Thescience and Practice of Pharmacy (loc. cit.).

The solid formulation according to the invention may also comprise oneor several flow regulators selected from the group consisting of silica,preferably colloidal anhydrous silica, calcium silicate, magnesiumsilicate, talc, and the like. Any other flow regulator known to theskilled person and found suitable for the solid formulation according tothe invention may also be incorporated into the solid formulationaccording to the invention. See also Remington, J. P. The science andPractice of Pharmacy (loc. cit.).

The solid formulation according to the invention may also comprise oneor several disintegrants selected from the group consisting ofcroscarmellose sodium, sodium starch glycolate, pregelatinised starch,cross-linked polyvinylpyrrolidone and the like. Any other disintegrantknown to the skilled person and found suitable for the solid formulationaccording to the invention may also form part of the solid formulationaccording to the invention. See also Remington, J. P. The science andPractice of Pharmacy (loc. cit.).

The solid formulation according to the invention may also comprise oneor several lubricants selected from the group consisting of magnesiumstearate, calcium stearate, glyceryl behenate, polyethylene glycol,stearic acid, talc and the like. Any other lubricant known to theskilled person and found suitable for the solid formulation according tothe invention may form part of the solid formulation according to theinvention. See also Remington, J. P. The science and Practice ofPharmacy (loc. cit.).

The invention preferably also relates to a solid formulation accordingto the invention, characterized in that the carriers are starch andlactose. The invention preferably also relates to a solid formulationaccording to the invention, characterized in that the lactose consistsof coarse particles greater than 200 μm in size. The person skilled inthe art knows other types of lactose which are suitable as well ascarrier according to the invention, e.g. fine lactose equal or smallerthan 200 μm in size or spray-dried lactose. Preferred is lactoseconsisting of coarse particles greater than 200 μm in size.

The invention preferably also relates to a solid formulation accordingto the invention, characterized in that the starch or various starchesare selected from the group consisting of native starch, gelatinizedstarch, partly gelatinized starch, starch powder, starch granules,chemically modified starch and swellable, physically modified starch.

The invention preferably also relates to a solid formulation accordingto the invention, characterized in that the starch is corn starch.

The invention preferably also relates to a solid formulation accordingto the invention, comprising 0.5 mg to 20 mg of pimobendan. The morepreferred solid formulation contains 1 to 10 mg of pimobendan. The evenmore preferred solid formulation contains 1.25 to 5 mg of pimobendan.Most preferred solid formulations contain 1.25 mg, 2.5 mg, 5 mg or 10 mgof pimobendan.

The invention preferably also relates to a solid formulation accordingto the invention, comprising a content of 1:10-1:40 of pimobendan inrelation to citric acid anhydride. The preferred ratio is 1:20.

The invention preferably also relates to a solid formulation accordingto the invention, characterized in that the weight of the whole solidformulation is in the range of 250 to 3000 mg, with a more preferredweight range of 500 mg to 2000 mg, and most preferred weight of 500 mg,1000 mg or 2000 mg.

The invention preferably also relates to a solid formulation accordingto the invention, characterized in that the solid formulation isproduced by a fluid-bed granulation process comprising or consisting ofthe steps:

-   -   a) an aqueous solution of pimobendan and a binder as defined        above is sprayed onto a solid carrier bed comprising one or        several carriers and/or excipients as defined above, flavor and        citric acid anhydride and    -   b) the mixture of a) is dried and    -   c) the mixture of b) is sieved and de-agglomerated and    -   d) a flow regulator is added to the mixture of c) and    -   e) a lubricant is added to the mixture of d) and    -   f) the mixture of e) is blended for uniformity of granules to        obtain final granules    -   and/or    -   g) the final granules off) are compressed to solid formulations.    -   Step g) is omitted if the solid formulation is a granule. If the        solid formulation is a tablet, step g) is carried out.

The invention preferably also relates to a solid formulation accordingto the invention, characterized in that the solid formulation isproduced by a fluid-bed granulation process comprising or consisting ofthe steps:

-   -   a) an aqueous solution of pimobendan and povidone is sprayed        onto a solid carrier bed comprising lactose, starch, flavor and        citric acid anhydride and    -   b) the mixture of a) is dried and    -   c) the mixture of b) is sieved and de-agglomerated and    -   d) a flow regulator is added to the mixture of c) and    -   e) a lubricant is added to the mixture of d) and    -   f) the mixture of e) is blended for uniformity of granules to        obtain final granules and/or    -   g) the final granules off) are compressed to solid formulations.

Step g) is omitted if the solid formulation is a granule. If the solidformulation is a tablet, step g) is carried out.

The invention preferably relates to a granule formulation as obtained bythe process above that can either be administered in the granular formor as tablets after compressing the final granules to tablets.Therefore, the solid formulation according to the invention preferablyis a granule (or a plurality of such granules) or a tablet. Theadministration of the granules can take place by mixing with food or byoffering the granules directly to the animal, e.g. in a bowl. Theapplication of the granular form will allow an individual dosing ofpimobendan according to the body weight of the animal.

The tablets according to the invention have surprising advantages. Thedissolution profile ensures immediate release of pimobendan.Surprisingly, it could be demonstrated that while compressing the finalgranules as mentioned above, a decrease in the dissolutioncharacteristics is not observed. By ensuring an immediate releaseprofile of pimobendan, the amount of drug to be administered can be keptas low as possible, thereby improving the safety profile, which isespecially important for long-term treatment.

Furthermore, the dosing accuracy of the tablet is excellent. This is dueto the fact that in accordance with the manufacturing process accordingto this invention, an excellent uniformity of pimobendan content isachieved. Furthermore, the tablets can be broken into two halves so thathalf the dose per tablet can be administered. Compared with the existinggelatin capsule, the dosing accuracy and compliance of both the animaland the animal owner are assured. This is even more important since thedrug is administered for a chronic condition and long-term treatment.

Also, the palatability of the tablet is excellent. More than 90% of thedogs to whom the tablet according to this invention was given acceptedthe tablet voluntarily with only the tablet offered in a bowl. Comparedwith the existing gelatin capsule, the ease of administration hasincreased compliance with the prescribed treatment regime. This isimportant since the drug is administered for a chronic condition.

The invention preferably also relates to a tablet according to theinvention, characterized in that the tablet is stable for at least 18months at 25.degree. C. and 60% relative humidity. In the examples,testing parameter assays are disclosed for degradation of pimobendan,dissolution, loss on drying, hardness and disintegration of the tablet.The tablets according to the invention are within the specificationlimits regarding degradation of pimobendan, dissolution, loss on drying,hardness and disintegration.

Suitable packaging materials for tablets according to the invention areselected from, but not limited to: aluminum/aluminum blisters, PVC/PVDCblisters, and HDPE (high density polyethylene bottles).

The invention preferably also relates to a tablet according to theinvention, characterized in that the tablet is oblong in shape. For sucha tablet, characteristics like crushing strength, disintegration,uniformity of weight and content uniformity fulfill the requirements ofthe European Pharmacopoeia (ISBN/ISSN 92-871-5106-7 of 4.sup.th Edition2004, Vol. 4.8, European Directorate for the Quality of Medicines(EDQM), European Pharmacopoeia, 226 avenue de Colmar, F-67029Strasbourg, France, http://www.pheur.org) and the United StatesPharmacopoeia (http://www.usp.org; in print: USP-NF, catalog No.2270001).

The invention preferably relates to a solid formulation, and mostpreferred a tablet according to the invention, characterized in that thesolid formulation or tablet comprising 0.5-20 mg pimobendan, preferablyof 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and further compriseslactose (35-50% by weight relative to the dry mass of the solidformulation/tablet=(w/w)), corn starch (25-50% w/w),croscarmellose-sodium (1-5%), citric acid (2.5-10% w/w), artificial beefflavor (5-30% w/w), polyvidone (1-5% w/w), colloidal anhydrous silica(0.1-1, preferably 0.1-0.5% w/w) and magnesium stearate (0.25-1.5% w/w),wherein the percentage by weight of pimobendan contains preferably about0.25% (w/w) and the sum of the percentages by weight of all ingredientsof the solid formulation including pimobendan is 100% (w/w). A skilledman is in a position to prepare such solid formulations, preferably atablet. Thus, the skilled man knows that he can add to 0.25% (w/w)pimobendan at most 32.625% (w/w) corn starch, 4% (w/w)croscarmellose-sodium 5% (w/w) citric acid, 20% (w/w) artificial beefflavor, 4% (w/w) polyvidone, colloidal, 0.5% (w/w) anhydrous silica, 1%(w/w) magnesium stearate if the amount of lactose to be 32.625% (w/w).Moreover, the skilled man also knows that if he decided to reduce theamount of the artificial beef flavor, for example, to the minimum of 5%(w/w), he can increase the amount of lactose, for example, to 47.625%(w/w). The invention also relates to a solid formulation, preferably atablet, comprising about 0.25% (w/w) pimobendan and any of the aboveother ingredients of the solid formulation, preferably the tablet, inthe range given above so that the sum of the amounts by weight of theindividual formulation ingredients is 100%.

The present invention is also directed to a solid formulation,preferably to a tablet, which comprises 1 mg pimobendan, 100-200 mglactose, 100-200 mg corn starch, 4-20 mg croscarmellose-sodium, 10-40 mgcitric acid anhydrous, 20-120 mg artificial beef flavor, 4-20 mgpolyvidone, 0.4-4 mg colloidal anhydrous silica, and 1-6 mg magnesiumstearate for each 400 mg of total weight of the solid formulation,preferably a tablet. According to a further embodiment of the presentinvention, the solid formulation, preferably the tablet, comprises 1 mgpimobendan, 120-180 mg lactose, 120-180 mg corn starch, 8-18 mgcroscarmellose-sodium, 15-30 mg citric acid anhydrous, 40-100 mgartificial beef flavor, 8-18 mg polyvidone, 0.5-2 mg colloidal anhydroussilica, and 2-5 mg magnesium stearate for each 400 mg of total weight ofthe solid formulation/tablet. For example, the present invention relatesto a solid formulation comprising for each 400 mg of total weight: 1 mgpimobendan, 20 mg citric acid anhydrous, 130.5 mg lactose, 130.5 mg cornstarch, 16 mg polyvidone, 16 mg croscarmellose-sodium, 80 mg artificialbeef flavor, 4 mg magnesium stearate, and 2 mg colloidal anhydroussilica. A skilled man is in a position to prepare such solidformulation/tablet. The skilled man also knows that he can vary theamount of each ingredient of the solid formulation/tablet within theranges given above in that the total weight of the solidformulation/tablet for each 1 mg pimobendan is 400 mg. For example, theamount of lactose may be 100, 101, 102, . . . 108, 109, 110 etc.; 111,112, . . . 118, 119, 120 etc.; 121, 122, . . . 128, 129, 120 etc.; 131,132, . . . 138, 139, 140 etc.; 141, 142, . . . 148, 149, 150 etc.; 151,152, . . . 158, 159, 160 etc.; 161, 162, . . . 168, 169, 170 etc.; 171,172, . . . 178, 179, 180 etc.; 108, 182, . . . 188, 189, 190 etc.; 191,192, . . . 198, 199, 200 mg for each 400 mg of total weight of the solidformulation, preferably a tablet, comprising about 1 mg pimobendan. Inthe same manner the amount of corn starch may be 100, 101, 102, . . .108, 109, 110 etc.; 111, 112, . . . 118, 119, 120 etc.; 121, 122, . . .128, 129, 120 etc.; 131, 132, . . . 138, 139, 140 etc.; 141, 142, . . .148, 149, 150 etc.; 151, 152, . . . 158, 159, 160 etc.; 161, 162, . . .168, 169, 170 etc.; 171, 172, . . . 178, 179, 180 etc.; 108, 182, . . .188, 189, 190 etc.; 191, 192, . . . 198, 199, 200 mg for each 400 mg oftotal weight of the solid formulation, preferably a tablet, comprisingabout 1 mg pimobendan. Furthermore, the amount of citric acid anhydrousmay be 10, 11, 12, . . . 18, 19, 20 etc.; 21, 22, . . . 28, 29, 30 etc.;31, 32, . . . 38, 39, 40 mg for each 400 mg of total weight of the solidformulation, preferably a tablet comprising about 1 mg pimobendan.Furthermore, the amount of artificial beef flavor may be 20, 21, 22, . .. 28, 29, 30 etc.; 31, 32, . . . 38, 39, 40 etc.; 41, 42, . . . 48, 49,50 etc.; 50, 51, 52, . . . 58, 59, 60 etc.; 61, 62, . . . 68, 69, 70etc.; 71, 72, . . . 78, 79, 80 etc., 81, 82, 83, . . . 88, 89, 90 etc.;91, 92, . . . 98, 99, 100 etc.; 101, 102, . . . 108, 109, 110 etc.; 111,112, . . . 118, 119, 120 mg for each 400 mg of total weight of the solidformulation, preferably a tablet, comprising about 1 mg pimobendan.Furthermore, the amount of polyyidone may be 4, 5, 6, . . . 8, 9, 10etc.; 11, 12, . . . 18, 19, 20 mg for each 400 mg of total weight of thesolid formulation, preferably a tablet, comprising about 1 mgpimobendan. Furthermore, the amount of croscarmellose-sodium may be 4,5, 6, . . . 8, 9, 10 etc.; 11, 12, . . . 18, 19, 20 mg for each 400 mgof total weight of the solid formulation, preferably a tablet,comprising 1 mg pimobendan. Furthermore, the amount of magnesiumstearate may be 1.0, 1.1, 1.2, . . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, . . .2.8, 2.9, 3.0 etc.; 3.1, 3.2, . . . 3.8, 3.9, 40 etc.; 4.0, 4.1, 4.2, .. . 4.8, 4.9, 5.0 etc.; 5.1, 5.2, . . . 5.8, 5.9, 6.0 mg for each 400 mgof total weight of the solid formulation, preferably a tablet,comprising about 1 mg pimobendan. Furthermore, the amount of colloidalanhydrous silica may be 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 1.0, 1.1, 1.2, . .. 1.8, 1.9, 2.0 etc.; 2.1, 2.2, . . . 2.8, 2.9, 3.0 etc.; 3.1, 3.2, . .. 3.8, 3.9, 4.0 mg for each 400 mg of total weight of the solidformulation, preferably a tablet, comprising about 1 mg pimobendan. Askilled man is in a position to prepare any of such inventive solidformulation, preferably as a tablet.

In another important embodiment, the invention relates to a fluid-bedgranulation process comprising the following steps:

-   -   a) an aqueous solution of pimobendan and a binder as defined        above is sprayed onto a solid carrier bed comprising one or        several carriers and/or excipients as defined above, flavor and        citric acid anhydride and    -   b) the mixture of a) is dried and    -   c) the mixture of b) is sieved and de-agglomerated and    -   d) a flow regulator is added to the mixture of c) and    -   e) a lubricant is added to the mixture of d) and    -   f) the mixture of e) is blended for uniformity of granules to        obtain final granules and/or    -   g) the final granules off) are compressed to solid formulations.

Step g) is omitted if the solid formulation is a granule. If the solidformulation is a tablet, step g) is carried out.

The invention preferably relates to a fluid-bed granulation processcomprising the following steps:

-   -   a) an aqueous solution of pimobendan and polyvidone is sprayed        onto a solid support comprising lactose, starch, flavor and        citric acid anhydride and    -   b) the mixture of a) is dried and    -   c) the mixture of b) is sieved and de-agglomerated and    -   d) a flow regulator is added to the mixture of c) and    -   e) a lubricant is added to the mixture of d) and    -   f) the mixture of e) is blended for uniformity of granules to        obtain final granules and/or    -   g) the final granules of f) are tableted.

Step g) is omitted if the solid formulation is a granule. If the solidformulation is a tablet, step g) is carried out.

Another embodiment is a method of prevention and/or treatment ofdiseases wherein cardiotonic, hypotensive and anti-thrombotic substanceshave a therapeutic benefit, comprising administering to a mammal in needof such treatment a therapeutically effective amount of a solidformulation according to the invention as disclosed above. Preferred isa method of prevention and/or treatment of congestive heart failure,comprising administering to a mammal in need of such treatment atherapeutically effective amount of a solid formulation according to theinvention as disclosed above. Most preferably, the method comprisesadministering a tablet according to the invention, characterized in thatthe tablet comprises 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, andfurther comprises lactose, corn starch, croscarmellose-sodium, citricacid preferably at an amount of 50 mg/g, artificial beef flavor,polyvidone, colloidal anhydrous silica and magnesium stearate.Preferably also, such treatment is by orally administering the solidformulation according to the invention.

The mammal according to the invention is preferably a mammal selectedfrom the group consisting of dogs, cats and rodents such as rabbits.

Furthermore, the invention relates to a method for manufacturing amedicament for the prevention and/or treatment of congestive heartfailure, characterized in that a solid formulation according to theinvention is used. Preferably, the invention relates to a method formanufacturing a medicament for the prevention and/or treatment ofcongestive heart failure, characterized in that a tablet consisting of1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan and further consisting oflactose, corn starch, croscarmellose-sodium, 50 mg/g citric acid,artificial beef flavor, polyvidone, colloidal anhydrous silica andmagnesium stearate is used.

The present invention furthermore relates to a kit, which comprises asolid formulation, preferably a tablet according to the presentinvention described herein, and a package leaflet or user instructionincluding the information concerning how the solid formulation,preferably the tablet, is to used via the oral route for the preventionand/or treatment of congestive heart failure in a mammal in need of suchprevention or treatment, preferably in a dog, cat or rodent.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as limiting the scope ofthe invention disclosed herein.

Example 1 Compositions

Composition A

Composition A mg/tablet mg/tablet mg/tablet 1.25 mg 2.5 mg 5.0 mgVolatile Ingredients chewable chewable chewable ingredient kg/batch (01)Pimobendan 1.250 2.500 5.000 0.175 (02) Citric acid anhydrous <200 μm25.000 50.000 100.00 3.500 (03) Starch 163.125 326.250 652.500 22.8375(04) Lactose, coarse 163.125 326.250 652.500 22.8375 (05) Polyvidone20.000 40.000 80.000 2.800 (06) Croscannellose Sodium 20.000 40.00080.000 2.800 (07) Artificial Powdered Beef Flavour 100.000 200.000400.000 14.000 (08) Silica, colloidal anhydrous 2.500 5.000 10.000 0.350(09) Magnesium stearate 5.000 10.000 20.000 0.700 (10) Purified water +500.000 1000.000 2000.000 − 70.000

Composition B

Composition B mg/tablet mg/tablet mg/tablet 1.25 mg 2.5 mg 5.0 mgVolatile Ingredients chewable chewable chewable ingredient kg/batchPimobendan 1.250 2.500 5.000 0.175 Citric acid anhydrous <200 μm 25.00050.000 100.000 3.500 Starch 163.125 326.250 652.500 22.8375 Lactose,coarse 238.125 476.250 952.500 22.8375 Polyvidon 20.000 40.000 80.0002.800 Croscarmellose Sodium 20.000 40.000 80.000 2.800 Meat Flavour25.000 50.000 100.000 14.000 Silica, colloidal anhydrous 2.500 5.00010.000 0.350 Magnesium stearate 5.000 10.000 20.000 0.700 Purifiedwater + 500.000 1000.000 2000.000 − 70.000

Example 2 Raw Materials

-   -   (01) Pimobendan    -   Function: Active ingredient    -   (02) Citric acid anhydrous <200 μm    -   Function: Diluent, Disintegrant    -   (03) Starch    -   Function: Carrier, Disintegrant    -   (04) Lactose coarse    -   Function: Carrier, Disintegrant    -   (05) Povidone    -   Function: Binder    -   (06) Croscarmellose Sodium    -   Function: Disintegrant    -   (07) Artificial Powdered Beef Flavor    -   Function: Flavor    -   (08) Silica, colloidal anhydrous    -   Function: Flow regulator, Disintegrant    -   (09) Magnesium stearate    -   Function: Lubricant    -   (10) Purified water    -   Function: Solvent

Example 3 Product Description

Appearance: brownish, oblong tablets, with break line.

Tablet Tablet Tablet Weight 500 mg 1000 mg 2000 mg Length About 19.0 mmAbout 24.0 mm About 25.0 mm Width About 7.0 mm About 7.5 mm About 15.0mm Thickness About 4.2 mm About 5.6 mm About 6.0 mm

Example 4 Manufacturing Process

-   -   1 batch=140000 tablets (1.25 mg Dosage)    -   1 batch=70000 tablets (2.50 mg Dosage)    -   1 batch=35000 tablets (5.00 mg Dosage)

1. 1. Granulating

Transfer in a suitable Granulator after prescreening: (01) Starch (e.g.18 mesh sieve) 22.8375 kg (02) Lactose (e.g. 18 mesh sieve) 22.8375 kg(03) Citric acid anhydrous (e.g. 18 mesh sieve) 3.500 kg (04)Croscarmellose sodium (e.g. 18 mesh sieve) 2.800 kg (05) Artificial BeefFlavour (e.g. 45 mesh sieve) 14.000 kg (05) Povidone (Spray solution)2.800 kg (06) UDCG 115 BS (Spray liquid) 0.175 kg Premix in thegranulator and granulate 68.950 kg Purified water (e.g. 16.8 kg, range:12.0-18.0 kg) is used as a solvent for the spray solution of povidoneand dispersion of pimobendan.

2. Screening

Screen the premixture 1. 68.950 kg 68.950 kg

3. Final Mixing

Add (07) Sillica, colloidal anhydrous (e.g. 25 mesh sieve)  0.350 kg(08) Magnesium stearate (e.g. 25 mesh sieve)  0.700 kg In a tumblingmixer, mix the screened premixture (2.) 70.000 kg and the twoingredients 70.000 kg

4. Compression

Using a rotary press, compress the final mixture (3.) 70.000 kg intotablets of 500 mg, 1000 mg, 2000 mg. 70.000 kg

5. Packaging

-   -   Transfer the tablets in a suitable container.    -   The tablets can be packed e.g. by blistering of the tablets in a        suitable machine.

Example 5 In Process Controls

1. Granules

1.1 Appearance: Brownish, white-speckled granules

1.2 Loss on Drying: Determine the loss on drying

-   -   e.g.: HR73; 3 g/105° C./5 min    -   Target: approx. 3.0%    -   Tolerance limits: below 5.0%

2. Tablets

2.1 Appearance: Brownish, white-speckled, oblong tablets with breakline

2.2 Weight uniformity:

1) 1.25 mg chewable Average weight: 475-525 mg 2) 2.5 mg chewableAverage weight: 950-1050 mg 3) 5 mg chewable Average weight: 1900-2100mg

2.3 Hardness: Determine the hardness

1) 1.25 mg Target: 140 N Tolerance: 60-250 N 2) 2.5 mg Target: 160 NTolerance: 60-250 N 3) 5.0 mg Target 190 N Tolerance: 60-300 N

2.4 Disintegration time: Determine the disintegration time according toUSP/EP

-   -   Tolerance limits: ≧15 minutes with water at 37° C., with disks

Example 6 Palatability Study

A study to investigate the palatability of pimobendan-containing tabletswas carried out. For a period of four days, two products were given totwenty or ten dogs, respectively, for voluntary uptake. For example, thefollowing formulations with a content of 5 mg/500 mg active ingredientwere examined:

Ch. 010122 (tablets with 10% Ch. 010123 (tablets with 10% content ofartificial beef flavor) content of artificial beef flavor) Pimobendan 5mg Pimobendan 5 mg (UD-CG 115 BS) (UD-CG 115 BS) Lactose 85.5 mg Lactose55.5 mg Corn starch 199.5 mg Corn starch 129.5 mg Croscarmellose- 20 mgCroscarmellose- 20 mg Sodium Sodium Citric acid 100 mg Citric acid 100mg Artificial Beef 50 mg Artificial Beef 150 mg Flavor Flavor Polyvidone25 mg Polyvidone 25 mg Macrogol 6000 15 mg Macrogol 6000 15 mg Total:500 mg Total: 500 mg

In case of Ch. 010123 in competition with the identical formulation ingranulated format, a voluntary uptake was observed in 36 out of 40possible opportunities (i.e. when offered to 10 dogs for 10 days). Thiscompares to an acceptance rate of 90.0%.

In case of Ch. 010222 in competition with a formulation in granulatedformat of equal quantity with 30% flavor, a voluntary uptake wasobserved in 31 out of 40 possible opportunities. This compares to anacceptance rate of 77.5%.

Example 7 Dissolution Profiles

Examples for representative dissolution profiles of the tablet accordingto this invention are as disclosed in FIG. 3.

Dissolution Profiles, Pimobendan 1.25 Mg Tablets Showing 95% ConfidenceIntervals of the Mean USP Apparatus 2 (Paddle), Rotation Speed 75 Rpm,Buffer pH 4.0 Comparison of Dissolution Profiles of Tablets which wereStored 1 and 6 Months at 40° C./75% in HDPE Bottles Batch No. PB020049

Examples for representative dissolution profiles of the tablet accordingto this invention are as disclosed in FIG. 4.

Dissolution Profiles, Pimobendan 1.25 Mg Tablets Showing 95% ConfidenceIntervals of the Mean USP Apparatus 2 (Paddle), Rotation Speed 75 Rpm,Buffer pH 4.0 Comparison of Dissolution Profiles of Tablets which wereStored 12 Days at 25° C./60% in Open Glass Bottles Batch No. PB010080Dissolution Profiles, Pimobendan 1.25 Mg Tablets Manufacturing Variable:Different Compression Forces

% Dissolved, mean (n = 6) Time Tablet hardness Batch No. (min) 70 N 105N 135 N 157 N 020102 10 82 82 81 84 20 98 97 97 98 30 101 99 100 100 45101 101 102 102

Examples for representative dissolution profiles of the tablet accordingto this invention are as disclosed in FIG. 5.

Dissolution Profiles, Pimobendan 2.5 Mg Tablets Showing 95% ConfidenceIntervals of the Mean USP Apparatus 2 (Paddle), Rotation Speed 75 Rpm,Buffer pH 4.0 Comparison of Dissolution Profiles of Tablets which wereStored 3 and 6 Months at 40° C./75% in Alu-Alu Blister Batch No.PB010076

Examples for representative dissolution profiles of the tablet accordingto this invention are as disclosed in FIG. 6.

Dissolution Profiles, Pimobendan 5.0 Mg Tablets Showing 95% ConfidenceIntervals of the Mean USP Apparatus 2 (Paddle), Rotation Speed 75 Rpm,Buffer pH 4.0 Comparison of Dissolution Profiles of Tablets which wereStored 6 Months at 40.Degree. C./75% in HDPE Bottles Batch No. PB020059

Examples for representative dissolution profiles of the tablet accordingto this invention are as disclosed in FIG. 7.

Dissolution Profiles, Pimobendan 5.0 Mg Tablets Showing 95% ConfidenceIntervals of the Mean USP Apparatus 2 (Paddle), Rotation Speed 75 Rpm,Buffer pH 4.0 Manufacturing Variable: Different Compression Forces BatchNo. 020205

% Dissolved, mean (n = 6) Tablet hardness Batch No. Time (min) 117 N 150N 186 N 222 N 020205 10 56 56 56 56 20 76 75 76 76 30 79 79 80 80 45 8080 81 81

Analytical Results for Pimobendan Chewable Tablet Batches Used inStability Study % dissolved in t = 30 minutes, mean (n = 6) TabletInitial 6 Months 6 Months 6 Months strength Batch No. Packaging value25° C./60% 30° C./70% 40° C./75% 1.25 mg  PB020049 HDPE bottle 97 95 9493 PB020049 Alu-Alu blister 95 93 94 PB020049 PVC/PVDC blister 94 93 93PB020050 HDPE bottle 94 92 93 91 PB020050 Alu-Alu blister 92 92 91PB020050 PVC/PVDC blister 93 93 92 PB020051 HDPE bottle 94 93 92 92PB020051 Alu-Alu blister 94 93 92 PB020051 PVC/PVDC blister 93 93 91 2.5mg PB020052 HDPE bottle 98 n.d. n.d. 93 PB020052 Alu-Alu blister n.d.n.d. 94 PB020052 PVC/PVDC blister n.d. n.d. 92 PB020053 HDPE bottle 97n.d. n.d. 91 PB020053 Alu-Alu blister n.d. n.d. 91 PB020053 PVC/PVDCblister n.d. n.d. 91 PB020054 HDPE bottle 97 n.d. n.d. 91 PB020054Alu-Alu blister n.d. n.d. 92 PB020054 PVC/PVDC blister n.d. n.d. 91 5.0mg PB020059 HDPE bottle 95 93 92 92 PB020059 Alu-Alu blister 93 92 92PB020059 PVC/PVDC blister 92 92 91 PB020060 HDPE bottle 92 91 90 89PB020060 Alu-Alu blister 91 91 90 PB020060 PVC/PVDC blister 91 91 89PB020061 HDPE bottle 94 91 91 89 PB020061 Alu-Alu blister 92 92 90PB020061 PVC/PVDC blister 91 91 89 n.d. = not determined

Example 8 Content Uniformity

Samples were taken from both the final blend before tableting and fromthe tableting process. The following results demonstrate the uniformityof pimobendan content.

Blend Uniformity Batch Assay [mg/g] % Target 0007LP-A 2.37 94.8 0007LP-B2.48 99.2 0007LP-C 2.43 97.2 0007LP-D 2.44 97.6 0007LP-E 2.47 98.80007LP-F 2.50 100.0 0007LP-G 2.49 99.6 0007LP-H 2.49 99.6 0007LP-I 2.50100.0 0007LP-J 2.43 97.2 Average 2.46 98.4 0008LP-A 2.41 96.4 0008LP-B2.48 99.2 0008LP-C 2.45 98.0 0008LP-D 2.45 98.0 0008LP-E 2.46 98.40008LP-F 2.43 97.2 0008LP-G 2.46 98.4 0008LP-H 2.44 97.6 0008LP-I 2.4798.8 0008LP-J 2.50 100.0 Average 2.46 98.2

Uniformity of Process Batch Assay [mg/g] % Target PM020080-1 2.48 99.2PM020080-2 2.52 100.8 PM020080-3 2.50 100.0 PM020080-4 2.52 100.8PM020080-5 2.49 99.6 PM020080-6 2.52 100.8 Average 2.51 100.2 PM020081-12.45 98.0 PM020081-2 2.51 100.4 PM020081-3 2.48 99.2 PM020081-4 2.4598.0 PM020081-5 2.47 98.8 PM020081-6 2.45 98.0 Average 2.47 98.7

Example 9 Accuracy of Broken Tablets

The tablets according to this invention were part of an contentuniformity test for the broken tablets. 10 tablets were taken from thebeginning, middle and end of the tabletting process and broken into twohalves. The pimobendan content was determined.

Pimobendan 5 mg tablet, batch no. 0000251607 Specification Start MiddleEnd CU min. (mg) ≧2.13 2.44 2.43 2.41 CU max. (mg) ≦2.87 2.61 2.57 2.57CU average (mg 2.25-2.62 2.52 2.51 2.50 RSD (%) ≦6.0  2.3 1.9 2.0

Pimobendan 1.25 mg tablet, batch no. 0000251604 Specification StartMiddle End CU min. (mg) ≧0.532 0.577 0.590 0.582 CU max. (mg) ≦0.7180.664 0.650 0.645 CU average (mg 0.563-0.656 0.621 0.621 0.616 RSD (%)≦6.0  5.4 3.4 3.6

Example 10 Stability Data After 24 Months (Dissolution/Assay ofPimobendan/Degradation of Pimobendan)

Product: Pimobendan chewable tablets 1.25 mg Batch No.: PB020049 HDPEbottle (m) PVC/PVDC (m) Aluminium blister (m) Dissolution 25° C./60° C.0 months 95 (min)-102 0 months 95 (min)-102 0 months 95 (min)-102(max)/97 (avg) ; 24 (max)/97 (avg) ; 24 (max)/97 (avg) ; 24 months96-99/97 months 96-99/97 months 92-96/94 30° C./70° C. 0 months 95(min)-102 0 months 95 (min)-102 0 months 95 (min)-102 (max)/97 (avg) ;24 (max)/97 (avg) ; 24 (max)/97 (avg) ; 24 months 96-97/97 months96-98/97 months 95-99/97 40° C./75° C. 0 months 95 (min)-102 0 months 95(min)-102 0 months 95 (min)-102 (max)/97 (avg) ; 6 (max)/97 (avg) ; 6(max)/97 (avg) ; 6 months 92-94/93 months 91-94/93 months 92-95/94 Assayof 25° C./60° C. 0 months 1.251; 24 0 months 1.251; 24 0 months 1.251;24 Pimobendan months 1.233 months 1.236 months 1.237 30° C./70° C. 0months 1.251; 24 0 months 1.251; 24 0 months 1.251; 24 months 1.229months 1.242 months 1.236 40° C./75° C. 0 months 1.251; 6 0 months1.251; 6 months 0 months 1.251; 6 months 1.221 1.214 months 1.231Degradation of 25° C./60° C. 0 months 1) <0.10 (K2006a) ; 0 months 1)<0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; Pimobendan 2) <0.10 (DU-2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS) ; 3) <0.10 (any 134 BS) ;3) <0.10 (any BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ;unspecified) ; 4) <0.10 (total; unspecified) ; 4) <0.10 (total; 24months 1) <0.10; 24 months 1) <0.10; 24 months 2) <0.10; 3) <0.10; 4)<0.10 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 4) <0.10 3) <0.10; 4)<0.10 30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10(K2006a) ; 0 months 1) <0.10 (K2006a) ; 2) <0.10 (DU- 2) <0.10 (DU-CG 2)<0.10 (DU-CG CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any BS); 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4)<0.10 (total) ; unspecified) ; 4) <0.10 (total) ; 24 months 1) 0.35; 24months 1) <0.10; 24 months 2) <0.10; 3) <0.10; 4) 0.35 2) <0.10; 3)<0.10; 1) <0.10; 2) 0.10; 4) <0.10 3) <0.10; 4) 0.10 40° C./75° C. 0months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1)<0.10 (K2006a) ; 2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any BS) ; 3) <0.10 (anyunspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ;unspecified) ; 4) <0.10 (total) ; 6 months 1) 0.55; 6 months 1) <0.10; 6months 1) 0.10; 2) <0.10; 3) <0.10; 4) 0.55 2) <0.10; 3) <0.10; 2) 0.11;3) <0.10; 4) 0.21 4) <0.10 Batch No.: PB020050 HDPE bottle (m) PVC/PVCD(m) Aluminium blister (m) Dissolution 25° C./60° C. 0 months 91 (min)-960 months 91 (min)-96 0 months 91 (min)-96 (max)/94 (avg) ; 24 (max)/94(avg) ; 24 (max)/94 (avg) ; 24 months 96-104/99 months 84-101/95 months92-96/94 30° C./70° C. 0 months 91 (min)-96 0 months 91 (min)-96 0months 91 (min)-96 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 (max)/94(avg) ; 24 months 94-102/97 months 93-102/97 months 97-105/99 40° C./75°C. 0 months 91 (min)-96 0 months 91 (min)-96 0 months 91 (min)-96(max)/94 (avg) ; 6 (max)/94 (avg) ; 6 (max)/94 (avg) ; 6 months 91-92/91months 91-93/92 months 91-92/91 Assay of 25° C./60° C. 0 months 1.231;24 0 months 1.231; 24 0 months 1.231; 24 Pimobendan months 1.224 months1.201 months 1.228 30° C./70° C. 0 months 1.231; 24 0 months 1.231; 24 0months 1.231; 24 months 1.213 months 1.217 months 1.230 40° C./75° C. 0months 1.231; 6 0 months 1.231; 6 months 0 months 1.231; 6 months 1.2051.202 months 1.215 Degradation of 25° C./60° C. 0 months 1) <0.10(K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ;Pimobendan 2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS); 3) <0.10 (any 134 BS) ; 3) <0.10 (any BS) ; 3) <0.10 (any unspecified); 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ; unspecified) ; 4)<0.10 (total) ; 24 months 1) <0.10; 24 months 1) <0.10; 24 months 2)<0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 4)<0.10 3) <0.10; 4) <0.10 30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 2) <0.10 (DU- 2)<0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3)<0.10 (any BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ;unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ; 24months 1) <0.37; 24 months 1) <0.10; 24 months1) <0.10; 2) <0.10; 3)<0.10; 4) <0.37 2) <0.10; 3) <0.10; 2) <0.10; 3) <0.10; 4) <0.10 4)<0.10 40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10(K2006a) ; 0 months 1) <0.10 (K2006a) ; 2) <0.10 (DU- 2) <0.10 (DU-CG 2)<0.10 (DU-CG CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3) <0.10 (any BS); 3) <0.10 (any unspecified) ; 4) <0.10 (total) ; unspecified) ; 4)<0.10 (total) ; unspecified) ; 4) <0.10 (total) ; 6 months 1) 0.58; 6months 1) <0.10; 6 months 1) <0.10; 2) <0.10; 3) <0.10; 4) 0.58 2)<0.10; 3) <0.10; 2) <0.10; 3) <0.10; 4) <0.10 4) <0.10 Batch No.:PB020051 HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Dissolution25° C./60° C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92(min)-95 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24months 92-100/96 months 94-101/97 months 91-100/95 30° C./70° C. 0months 92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95 (max)/94(avg) ; 24 (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 months 92-99/96months 95-98/97 months 92-100/97 40° C./75° C. 0 months 92 (min)-95 0months 92 (min)-95 0 months 92 (min)-95 (max)/94 (avg) ; 6 (max)/94(avg) ; 6 (max)/94 (avg) ; 6 months 91-93/92 months 90-92/91 months91-94/92 Assay of 25° C./60° C. 0 months 1.230; 24 0 months 1.230; 24 0months 1.230; 24 Pimobendan months 1.222 months 1.225 months 1.228 30°C./70° C. 0 months 1.230; 24 0 months 1.230; 24 0 months 1.230; 24months 1.214 months 1.221 months 1.230 40° C./75° C. 0 months 1.230; 6 0months 1.230; 6 months 0 months 1.230; 6 months 1.210 1.202 months 1.218Degradation of 25° C./60° C. 0 months 1) <0.10 (K2006a) ; 0 months 1)<0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; Pimobendan 2) <0.10 (DU-2) <0.10 (DU-CG 2) <0.10 (DU-GG CG 134 134 BS) ; 3) <0.10 (any 134 BS) ;3) <0.10 (any BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ;unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ; 24months 1) <0.10; 24 months 2) <0.10; 3) <0.10; 4) <0.10 1) <0.10; 2)<0.10; 3) <0.10; 4) <0.10 30° C./7° C. 0 months 1) <0.10 (K2006a) ; 0months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 2) <0.10 (DU- 2)<0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3)<0.10 (any BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ;unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ; 24months 1) <0.33; 24 months 2) <0.10; 3) <0.10; 4) 0.33 1) <0.10; 2)<0.10; 3) <0.10; 4) <0.10 40° C./75° C. 0 months 1) <0.10 (K2006a) ; 0months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 2) <0.10 (DU- 2)<0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS) ; 3) <0.10 (any 134 BS) ; 3)<0.10 (any BS) ; 3) <0.10 (any unspecified) ; 4) <0.10 (total) ;unspecified) ; 4) <0.10 (total) ; unspecified) ; 4) <0.10 (total) ; 6months 1) <0.54; 6 months 1) <0.10; 2) <0.10; 3) <0.10; 4) <0.54 2)0.10; 3) <0.10; 4) 0.10

Product: Pimobendan chewable tablets 2.5 mg Batch No.: PB020052 HDPEbottle (m) PVC/PVDC (m) Aluminium blister (m) Dissolution 30° C./70° C.0 months 97 (min)-99 0 months 97 (min)-99 0 months 97 (min)-99 (max)/98(avg) ; 12 (max)/98 (avg) ; 12 (max)/98 (avg) ; 12 Months 93-95/94months 93-94/94 months 94-97/96 40° C./75° C. 0 months 97 (min)-99 0months 97 (min)-99 0 months 97 (min)-99 (max)/98 (avg) ; 6 (max)/98(avg) ; 6 (max)/98 (avg) ; 6 months 93-94/93 months 91-93/92 months93-95/94 Assay of 30° C./70° C. 0 months 2.49; 12 0 months 2.49; 12months 0 months 2.49; 12 Pimobendan months 2.49 2.47 months 2.50 40°C./75° C. 0 months 2.49; 6 0 months 2.49; 6 months 0 months 2.49; 6months months 2.41 2.41 2.45 Degradation of 30° C./7° C. 0 months 0months 0 months Pimobendan 1) <0.10 (K2006a) ; 1) <0.10 (K2006a) ; 1)<0.10 (K2006a) ; 2) <0.10 (UDCG 134 2) <0.10 (UDCG 134 BS) ; 2) <0.10(UDCG 134 BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (anyunspecified) ; unspecified) ; unspecified) ; 4) <0.10 (total) ; 12 4)<0.10 (total) ; 12 months 4) <0.10 (total) ; 12 months 1) <0.10; 1)<0.10; 2) <0.10; months 1) <0.10; 2) <0.10; 3) <0.10; 3) <0.10; 4) <0.102) <0.10; 3) <0.10; 4) <0.10 4) <0.10 40° C./75° C. 0 months 0 months 0months 1) <0.10 (K2006a) ; 1) <0.10 (K2006a) ; 1) <0.10 (K2006a) ; 2)<0.10 (UDCG 134 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134 BS) ; 3)<0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any unspecified) ; unspecified); unspecified) ; 4) <0.10 (total) ; 6 4) <0.10 (total) ; 6 months 4)<0.10 (total) ; 6 months months 1) <0.10; 1) 0.43; 2) <0.10; 3)<0.10; 1) <0.10; 2) <0.10; 2) <0.10; 3) <0.10; 4) 0.43 3) <0.10; 4)<0.10 4) <0.10 Batch No.: PB020053 HDPE bottle (m) PVC/PVCD (m)Aluminium blister (m) Dissolution 30° C./70° C. 0 months 96 (min)-98 0months 96 (min)-98 0 months 96 (min)-98 (max)/97 (avg) ; 12 (max)/97(avg) ; 12 (max)/97 (avg) ; 12 months 92-94/93 months 90-93/92 months91-95/93 40° C./75° C. 0 months 96 (min)-98 0 months 96 (min)-98 0months 96 (min)-98 (max)/97 (avg) ; 6 (max)/97 (avg) ; 6 (max)/97 (avg); 6 months 89-93/91 months 91-91/91 months 90-92/91 Assay of 30° C./70°C. 0 months 2.44; 12 0 months 2.44; 12 months 0 months 2.44; 12Pimobendan months 2.44 2.41 months 2.46 40° C./75° C. 0 months 2.44; 6 0months 2.44; 6 months 0 months 2.44; 6 months months 2.41 2.40 2.40Degradation of 30° C./7° C. 0 months 0 months 0 months Pimobendan 1)<0.10 (K2006a) ; 1) <0.10 (K2006a) ; 1) <0.10 (K2006a) ; 2) <0.10 (UDCG134 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134 BS) ; 3) <0.10 (any 3)<0.10 (any BS) ; 3) <0.10 (any unspecified) ; unspecified) ;unspecified) ; 4) <0.10 (total) ; 12 4) <0.10 (total) ; 12 months 4)<0.10 (total) ; 12 months 1) <0.10; 1) <0.10; 2) <0.10; months 1) <0.10;2) <0.10; 3) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10; 4) <0.10 4)<0.10 40° C./75° C. 0 months 0 months 0 months 1) <0.10 (K2006a) ; 1)<0.10 (K2006a) ; 1) <0.10 (K2006a) ; 2) <0.10 (UDCG 134 2) <0.10 (UDCG134 BS) ; 2) <0.10 (UDCG 134 BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3)<0.10 (any unspecified) ; unspecified) ; unspecified) ; 4) <0.10 (total); 6 4) <0.10 (total) ; 6 months 4) <0.10 (total) ; 6 months months 1)<0.10; 1) 0.39; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 2) <0.10; 3)<0.10; 4) 0.39 3) <0.10; 4) <0.10 4) <0.10 Batch No.: PB020054 HDPEbottle (m) PVC/PVDC (m) Aluminium blister (m) Dissolution 30° C./70° C.0 months 96 (min)-98 0 months 96 (min)-98 0 months 96 (min)-98 (max)/97(avg) ; 12 (max)/97 (avg) ; 12 (max)/97 (avg) ; 12 months 93-95/94months 90-93/91 months 93-94/94 40° C./75° C. 0 months 96 (min)-98 0months 96 (min)-98 0 months 96 (min)-98 (max)/97 (avg) ; 6 (max)/97(avg) ; 6 (max)/97 (avg) ; 6 months 90-92/91 months 90-92/91 months91-93/92 Assay of 30° C./70° C. 0 months 2.45; 12 0 months 2.45; 12months 0 months 2.45; 12 Pimobendan months 2.47 2.45 months 2.44 40°C./75° C. 0 months 2.45; 6 0 months; 6 months 2.39 0 months 2.45; 6months months 2.40 2.41 Degradation of 30° C./7° C. 0 months 0 months 0months Pimobendan 1) <0.10 (K2006a) ; 1) <0.10 (K2006a) ; 1) <0.10(K2006a) ; 2) <0.10 (UDCG 134 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG134 BS) ; 3) <0.10 (any 3) <0.10 (any BS) ; 3) <0.10 (any unspecified) ;unspecified) ; unspecified) ; 4) <0.10 (total) ; 12 4) <0.10 (total) ;12 months 4) <0.10 (total) ; 12 months 1) <0.10; 1) <0.10; 2) <0.10;months 1) <0.10; 2) <0.10; 3) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3)<0.10; 4) <0.10 4) <0.10 40° C./75° C. 0 months 0 months 0 months 1)<0.10 (K2006a) ; 1) <0.10 (K2006a) ; 1) <0.10 (K2006a) ; 2) <0.10 (UDCG134 2) <0.10 (UDCG 134 BS) ; 2) <0.10 (UDCG 134 BS) ; 3) <0.10 (any 3)<0.10 (any BS) ; 3) <0.10 (any unspecified) ; unspecified) ;unspecified) ; 4) <0.10 (total) ; 6 4) <0.10 (total) ; 6 months 4) <0.10(total) ; 6 months months 1) <0.10; 1) 0.36; 2) <0.10; 3) <0.10; 1)<0.10; 2) <0.10; 2) <0.10; 3) <0.10; 4) 0.36 3) <0.10; 4) <0.10 4) <0.10

Product: Pimobendan chewable tablets 5 mg Batch No.: PB020059 HDPEbottle (m) PVC/PVDC (m) Aluminium blister (m) Dissolution 25° C./60% 0months 94 (min)-96 0 months 94 (min)-96 0 months 94 (min)-96 (max)/95(avg) ; (max)/95 (avg) ; 24 (max)/95 (avg) ; 24 24 months 83-90/88months 83-92/88 months 85-89/87 30° C./70° C. 0 months 94 (min)-96 0months 94 (min)-96 0 months 94 (min)-96 (max)/95 (avg) ; (max)/95 (avg); 24 (max)/95 (avg) ; 24 24 months 83-95/89 months 82-97/88 months83-91/87 40° C./75° C. 0 months 94 (min)-96 0 months 94 (min)-96 0months 94 (min)-96 (max)/95 (avg) ; 6 (max)/95 (avg) ; 6 months (max)/95(avg) ; 6 months 91-92/91 90-92/91 months 81-93/92 Assay of 25° C./60% 0month 4.95; 24 0 month 4.95; 24 month 0 month 4.95; 24 month Pimobendanmonth 4.94 4.92 4.92 30° C./70° C. 0 month 4.95; 24 0 month 4.95; 24month 0 month 4.95; 24 month month 4.90 4.92 4.96 40° C./75° C. 0 month4.95; 6 0 month 4.95; 6 month 0 month 4.95; 6 month month 4.88 4.91 4.95Degradation of 25° C./60% 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10(K2006a) ; 0 months 1) <0.10 (K2006a) ; Pimobendan 2) <0.10 2) <0.10(UD-CG 2) <0.10 (UD- (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134BS) ; 3) <0.10 <0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4)unspecified) ; 4) (total) ; 24 months 1) <0.10 (total) ; 24 months <0.10(total) ; 24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) months 1)<0.10; 2) 4) <0.10 <0.10; 4) <0.10 <0.10; 3) <0.10; 4) <0.10 30° C./7°C. 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1)<0.10 (K2006a) ; 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS) ;3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10 <0.10 (any unspecified); 4) <0.10 (any unspecified) ; 4) unspecified) ; 4) (total) ; 24months 1) <0.10 (total) ; 24 months <0.10 (total) ; 24 <0.10; 2) <0.10;3) <0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4) <0.10 <0.10; 4)<0.10 <0.10; 3) <0.10; 4) <0.10 40° C./75° C. 0 months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 2) <0.10 2)<0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (anyCG 134 BS) ; 3) <0.10 <0.10 (any unspecified) ; 4) <0.10 (anyunspecified) ; 4) unspecified) ; 4) (total) ; 6 months 1) 0.23; <0.10(total) ; 6 months <0.10 (total) ; 6 2) <0.10; 3) <0.10; 4) 1) <0.10; 2)<0.10; 3) months 1) <0.10; 2) 0.23 <0.10; 4) <0.10 <0.10; 3) <0.10; 4)<0.10 Batch No.: PB020060 HDPE bottle (m) Aluminium blister (m) PVC/PVCD(m) Dissolution 25° C./60% 0 months 91 (min)-94 0 months 91 (min)-94 0months 91 (min)-94 (max)/92 (avg) ; (max)/92 (avg) ; 24 (max)/92 (avg) ;24 24 months 85-90/87 months 84-90/86 months 82-88/86 30° C./70° C. 0months 91 (min)-94 0 months 91 (min)-94 0 months 91 (min)-94 (max)/92(avg) ; (max)/92 (avg) ; 24 (max)/92 (avg) ; 24 24 months 85-90/87months 82-90/87 months 86-90/88 40° C./75° C. 0 months 94 (min)-96 0months 91 (min)-94 0 months 91 (min)-94 (max)/95 (avg) ; 6 (max)/92(avg) ; 6 months (max)/92 (avg) ; 6 months 88-89/89 88-90/89 months89-92/90 PVC/PVDC (m) Assay of 25° C./60% 0 month 4.87; 24 0 month 4.87;24 month 0 month 4.87; 24 month Pimobendan month 4.88 4.86 4.90 30°C./70° C. 0 month 4.87; 24 0 month 4.87; 24 month 0 month 4.84; 24 monthmonth 4.83 4.86 4.89 40° C./75° C. 0 month 4.87; 6 0 month 4.87; 6 month0 month 4.87; 6 month month 4.86 4.87 4.86 PVC/PVCD (m) Degradation of25° C./60% 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0months 1) <0.10 (K2006a) ; Pimobendan 2) <0.10 2) <0.10 (UD-CG 2) <0.10(UD- (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10<0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4) unspecified) ;4) (total) ; 24 months 1) <0.10 (total) ; 24 months <0.10 (total) ; 24<0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4)<0.10; <0.10; 4) <0.10; <0.10; 3) <0.10; 4) <0.10; 30° C./7° C. 0months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1)<0.10 (K2006a) ; 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS) ;3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10 <0.10 (any unspecified); 4) <0.10 (any unspecified) ; 4) unspecified) ; 4) (total) ; 24months 1) <0.10 (total) ; 24 months <0.10 (total) ; 24 <0.10; 2) <0.10;3) <0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4) <0.10; <0.10; 4)<0.10; <0.10; 3) <0.10; 4) <0.10; 40° C./75° C. 0 months 1) <0.10(K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 2)<0.10 2) <0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS) ; 3) 134 BS) ; 3)<0.10 (any CG 134 BS) ; 3) <0.10 <0.10 (any unspecified) ; 4) <0.10 (anyunspecified) ; 4) unspecified) ; 4) (total) ; 24 months 1) <0.10 (total); 6 months <0.10 (total) ; 6 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2)<0.10; 3) months 1) <0.10; 2) 4) <0.10; 6 months 1) <0.10; 4) <0.10<0.10; 3) <0.10; 4) 0.22; 2) <0.10; 3) <0.10; <0.10 4) 0.22 Batch No.:PB020061 HDPE bottle (m) Aluminium blister (m) PVC/PVDC (m) Dissolution25° C./60% 0 months 92 (min)-95 0 months 92 (min)-95 0 months 92(min)-95 (max)/94 (avg) ; (max)/94 (avg) ; 24 (max)/94 (avg) ; 24 24months 83-90/87 months 86-91/88 months 65-92/84 30° C./70° C. 0 months92 (min)-95 0 months 92 (min)-95 0 months 92 (min)-95 (max)/94 (avg) ;(max)/94 (avg) ; 24 (max)/94 (avg) ; 24 24 months 84-88/87 months81-87/85 months 88-91/90 40° C./75° C. 0 months 92 (min)-95 0 months 92(min)-95 0 months 92 (min)-95 (max)/94 (avg) ; 6 (max)/94 (avg) ; 6months (max)/94 (avg) ; 6 months 88-90/89 88-90/89 months 88-91/90PVC/PVCD (m) Assay of 25° C./60% 0 month 4.87; 24 0 month 4.87; 24 month0 month 4.87; 24 month Pimobendan month 4.83 4.85 4.88 30° C./70° C. 0month 4.87; 24 0 month 4.87; 24 month 0 month 4.87; 24 month month 4.824.80 4.90 40° C./75° C. 0 month 4.87; 6 0 month 4.87; 6 month 0 month4.87; 6 month month 4.83 4.82 4.88 PVC/PVDC (m) Degradation of 25°C./60% 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0months 1) <0.10 (K2006a) ; Pimobendan 2) <0.10 2) <0.10 (UD-CG 2) <0.10(UD- (UD-CG 134 BS) ; 3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10<0.10 (any unspecified) ; 4) <0.10 (any unspecified) ; 4) unspecified) ;4) (total) ; 24 months 1) <0.10 (total) ; 24 months <0.10 (total) ; 24<0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4)<0.10; <0.10; 4) <0.10 <0.10; 3) <0.10; 4) <0.10; 30° C./7° C. 0months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1)<0.10 (K2006a) ; 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS) ;3) 134 BS) ; 3) <0.10 (any CG 134 BS) ; 3) <0.10 <0.10 (any unspecified); 4) <0.10 (any unspecified) ; 4) unspecified) ; 4) (total) ; 24months 1) <0.10 (total) ; 24 months <0.10 (total) ; 24 <0.10; 2) <0.10;3) <0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4) <0.10; <0.10; 4)<0.10; <0.10; 3) <0.10; 4) <0.10; 40° C./75° C. 0 months 1) <0.10(K2006a) ; 0 months 1) <0.10 (K2006a) ; 0 months 1) <0.10 (K2006a) ; 2)<0.10 2) <0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS) ; 3) 134 BS) ; 3)<0.10 (any CG 134 BS) ; 3) <0.10 <0.10 (any unspecified) ; 4) <0.10 (anyunspecified) ; 4) unspecified) ; 4) (total) ; 6 months 1) 0.22; <0.10(total) ; 6 months <0.10 (total) ; 6 2) <0.10; 3) <0.10; 4) 1) <0.10; 2)<0.10; 3) months 1) <0.10; 2) 0.22 <0.10; 4) <0.10 <0.10; 3) <0.10; 4)<0.10

1. A solid formulation comprising a homogenous dispersion of: pimobendanor a pharmaceutically acceptable salt thereof; a polyvalent acidselected from the group consisting of citric acid, acetic acid, maleicacid, tartaric acid or their anhydrides; and a flavor acceptable tosmall animals; wherein the flavor is homogenously dispersed within suchsolid formulation.
 2. The solid formulation according to claim 1,further comprising one or more pharmaceutically acceptable carriersand/or excipients.
 3. The solid formulation according to claim 1,wherein the one or several excipients are selected from the groupconsisting of diluents, disintegrants, carriers, binders, flowregulators, lubricants and solvents.
 4. The solid formulation accordingto claim 2, wherein the binder is selected from the group consisting ofpolyvidone/povidone, methylcellulose, hydroxypropylmethylcellulose(HPMC), hydroxymethylcellulose, starch and gelatine.
 5. The solidformulation according to claim 2, wherein the disintegrant/carrier isselected from the group consisting of lactose, starch, cellulose,microcrystalline cellulose and methylcellulose.
 6. The solid formulationaccording to claim 5, wherein the lactose consists of coarse particlesgreater than 200 μm in size.
 7. The solid formulation according to claim2, wherein the starch or various starches are selected from the groupconsisting of native starch, gelatinized starch, partly gelatinizedstarch, starch powder, starch granules, chemically modified starch andswellable physically modified starch.
 8. The solid formulation accordingto claim 2, wherein the disintegrant is selected from the groupconsisting of croscarmellose sodium, sodium starch glycolate,pregelatinised starch and cross-linked polyvinylpyrrolidone.
 9. Thesolid formulation according to claim 2, wherein the flow regulator isselected from the group consisting of silica, preferably colloidalanhydrous silica, calcium silicate, magnesium silicate and talc.
 10. Thesolid formulation according to claim 2, wherein the lubricant isselected from the group consisting of magnesium stearate, calciumstearate, glyceryl behenate, polyethylene glycol, stearic acid and talc.11. The solid formulation according to claim 2, wherein the flavor isselected from the group consisting of artificial beef flavors,artificial chicken flavors, pork liver extract, artificial meat flavorand honey flavor.
 12. The solid formulation according to claim 1,further comprising 0.5 to 20 mg of pimobendan.
 13. The solid formulationaccording to claim 1, wherein the content of pimobendan in relation tocitric acid anhydrous is 1:10 to 1:40.
 14. The solid formulationaccording to claim 1, wherein the weight of the whole solid formulationis in the range of 250 mg to 3000 mg.
 15. The solid formulationaccording to claim 1, wherein the solid formulation is a tablet or agranule.
 16. The solid formulation according to claim 1, wherein thesolid formulation is a tablet and consists of 1.25 mg, 2.5 mg, 5 mg or10 mg pimobendan, and further consists of lactose, corn starch,croscarmellose-sodium, citric acid, artificial beef flavor, polyvidone,colloidal anhydrous silica and magnesium stearate.
 17. The solidformulation according to claim 1, wherein the solid formulation is atablet and consists of 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, andfurther consists of 35 to 50% (w/w) lactose, 25 to 50% (w/w) cornstarch, 1 to 5% (w/w) croscarmellose-sodium, 2.5 to 10% (w/w) citricacid, 5 to 30% (w/w) artificial beef flavor, 1 to 5% (w/w) polyvidone,0.1 to 1% (w/w) colloidal anhydrous silica and 0.25 to 1.5% (w/w)magnesium stearate.
 18. A method of prevention and/or treatment ofcongestive heart failure in a mammal, the method comprisingadministering the solid formulation of claim 1 to the mammal.
 19. Afluid-bed granulation process comprising: a) spraying an aqueousdispersion of pimobendan and an aqueous solution of a binder onto asolid support comprising one or several carriers and/or excipients,flavor and citric acid anhydrous; b) drying the mixture of a); c)sieving and de-agglomerating the mixture of b); d) adding a flowregulator to the mixture of c); e) adding a lubricant to the mixture ofd); f) blending the mixture of e) for uniformity of granules to obtainfinal granules; and g) compressing the final granules off) to tablets.20. The fluid-bed granulation process according to claim 19, wherein thebinder of step a) is povidone, and the solid support of step a)comprises lactose, starch, flavor and citric acid anhydrous.